Bicyclic metabotropic glutamate receptor ligands

ABSTRACT

The present invention provides bicyclic metabotropic glutamate receptor ligands, as well as compositions comprising such ligands, and and methods for their use.

PRIORITY OF INVENTION

[0001] This application claims priority under 35 U.S.C. §119(e) fromUnited States Provisional Application No. 60/052,972, filed Jul. 181997, and from United States Provisional Application No. 60/064,304,filed Nov. 5, 1997.

BACKGROUND OF THE INVENTION

[0002] L-Glutamate, which is the most abundant neurotransmitter in theCNS, mediates the major excitatory pathway in mammals, and thus isreferred to as an excitatory amino acid (EAA). The receptors thatrespond to glutamate are called EAA receptors. The EAA receptors are ofgreat physiological importance playing a role in a variety ofphysiological processes, such as long-term potentiation (learning andmemory), the development of synaptic plasticity, motor control,respiration, cardiovascular regulation, emotional states and sensoryperception.

[0003] The excessive or inappropriate stimulation of EAA receptors leadsto neuronal cell damage or loss by way of a mechanism known asexcitotoxicity. The medical consequence of such neuronal degenerationmakes the abatement of these degenerative neurological processes animportant therapeutical goal.

[0004] EAA receptors are classified into two general types. Receptorsthat are directly coupled to the opening of cation channels in the cellmembranes of the neuron are termed “ionotropic”. The second type ofreceptor is the G-protein or second messenger-linked “metabotropic” EAAreceptor. This second type is coupled to multiple second messengersystems that lead to enhanced phosphoinositide hydrolysis, activation ofphospholipase D, increases or decreases in cAMP formation, and changesin ion channel function. The metabotropic glutamate receptors (mGluR)have been distinguished pharmacologically from the ionotropic glutamatereceptors by the use of the metabotropic glutamate-selective antagonist(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, generally throughmeasurements involving phosphoinositide hydrolysis or Ca²⁺ mobilization.To date the use of expression cloning techniques has led to theidentification of eight mGluR subtypes, which have been placed intothree major categories (Groups) based on their molecular structure,signal transduction mechanisms, and pharmacological properties. Group ImGluRs (mGluR1 and 5) are coupled to phosphoinositide (PI) hydrolysis,whereas Group II (mGluR2 and 3) and Group III (mGluR4, 6, 7, and 8) arenegatively linked to adenylyl cyclase activity.

[0005] Glutamate receptors play a role in numerous neurological,neurodegenerative, psychiatric, and psychological disorders, and avariety of mammalian disease states are associated with “abnormalactivity” of these receptors. As used herein, the term “abnormalactivaty” includes either an increase or a decrease in activation of thereceptors as compared to normal function in said mammal. For example,metabotropic glutamate receptor ligands should be useful in thetreatment of diseases or conditions including epilepsy, cerebralischemia, pain, anxiety, spinal cord injury, chronic neurodegenerativediseases (e.g. Alzheimer's disease), Lou Gherig's disease (ALS),Parkinson's disease, Multiple Sclerosis and other diseases or conditionsthat result in progressive loss of neuronal cells and or cellularfunction.

[0006] In order to better characterize the roles of mGluRs inphysiological processes, there is a need to identify novel, highaffinity compounds that are mGluR Group or subtype specific. Suchcompounds are needed for use as pharmacological tools for the furtherinvestigation of mGluR function, and should be useful as therapeuticagents for the treatment of diseases or conditions associated withabnormal activity of metabotropic glutamate receptors.

SUMMARY OF THE INVENTION

[0007] The present invention provides compounds that are ligands formetabotropic glutamate receptors. Accordingly there is provided acompound of the invention which is a bicyclic compound of formula I:

[0008] wherein

[0009] R¹, R², R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are each independentlyhydrogen, carboxy, tetrazolyl, —SO₂OH, —PO(OH)₂, —B(OH)₂, (Cl-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, cyano, halo,—CONR_(a)R_(b), —NR_(c)Rd_(d)—SR_(e), aryl, heteroaryl,aryl(C₁-C₆)alkyl, diaryl(C₁-C₆)alkyl, or heteroaryl(C₁-C₆)alkyl, whereinany aryl or heteroaryl may optionally be substituted with 1, 2 or 3substituents selected from the group consisting of halo, hydroxy,(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, cyano, nitro, trifluoromethyl, trifluoromethoxy,and carboxy;

[0010] R⁵ is carboxy, tetrazolyl, (C₁-C₆)alkoxycarbonyl, —SO₂OH,—B(OH)₂, or —PO(OH)₂;

[0011] R⁶ is hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl,heteroaryl(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl, or (C₁-C₆)alkanoyl;

[0012] X is absent (a direct or single bond connects C₃ and C₄), OXy(—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—SO₂—), —C(R_(f))(R_(g))—,seleno (—Se—), —P(R_(x))—, or —N(R_(x))—, wherein R_(x) is hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, aryl, aryl(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl, or aryl(C₁-C₆)alkoxycarbonyl;

[0013] each R_(a) R_(b) and R_(c) is independently hydrogen,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl,heteroaryl, benzyl, or phenethyl;

[0014] each R_(c) or R_(d) is independently hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkyny, (C₁-C₆)alkanoyl, aryl,heteroaiyl, benzyl, or phenethyl; or R_(c) and R_(d) together with thenitrogen to which they are attached are triazolyl, imidazolyl,oxazolidinyl, isoxazolidinyl, pyrrolyl, morpholino, piperidino,pyrrolidino, pyrazolyl, indolyl, or tetrazolyl;

[0015] R_(f) and R_(g) are each independently hydrogen, carboxy,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, cyano, halo, —CONR_(h)R_(i), —NR_(j)R_(k),—SR_(m), aryl, heteroaryl, aryl(C₁-C₆)alkyl, or heteroaryl(C₁-C₆)alkyl,wherein any aryl or heteroaryl may optionally be substituted with 1, 2or 3 substituents selected from the group consisting of halo, hydroxy,(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, cyano, nitro, trifluoromethyl, trifluoromethoxy,and carboxy; or R_(f) and R_(g) together are oxo (═O) or thioxo (═S);

[0016] each R_(h), and R_(i), and R_(m) is independently hydrogen,(C₁-C6)alkyl, (C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl,heteroaryl, benzyl, or phenethyl; and

[0017] each R_(j) or R_(k) is independently hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkanoyl,aryl, heteroaryl, benzyl, or phenethyl; or R_(j) and R_(k) together withthe nitrogen to which they are attached are triazolyl, imidazolyl,oxazolidinyl, isoxazolidinyl, pyrrolyl, morpholino, piperidino,pyrrolidino, pyrazolyl, indolyl, or tetrazolyl;

[0018] or a pharmaceutically acceptable salt or prodrug thereof;

[0019] wherein at least one of R₁, R², R³, R⁴, R⁹, and R¹⁰ is carboxy,tetrazolyl, —SO₂OH, —PO(OH)₂, or —B(OH)₂.

[0020] The invention also provides a pharmaceutical compositioncomprising a compound of formula I, or a pharmaceutically acceptablesalt or prodrug thereof, in combination with a pharmaceuticallyacceptable diluent or carrier.

[0021] Additionally, the invention provides a therapeutic method forpreventing or treating a pathological condition or symptom in a mammal,such as a human, which is associated with abnormal activity ofmetabotropic glutamate receptors, comprising administering to a mammalin need of such therapy, an effective amount of a compound of formula I,or a pharmaceutically acceptable salt or prodrug thereof.

[0022] The invention provides a compound of formula I for use in medicaldiagnosis or therapy (preferably for use in treating a pathologicalcondition or symptom in a mammal, such as a human, associated withabnormal activity of metabotropic glutamate receptors), as well as theuse of a compound of formula I for the manufacture of a medicament forthe treatment of a pathological condition or symptom in a mammal, suchas a human, which is associated with abnormal activity of metabotropicglutamate receptors.

[0023] The invention provides a method for binding a compound of formulaI to metabotropic glutamate receptors comprising contacting mammaliantissue comprising said receptors, in vivo or in vitro, with an amount ofa compound of formula I effective to bind to said receptors. Tissuecomprising ligand bound metabotropic glutamate receptors can be used tomeasure the selectivity of test compounds for specific mGluR Groups orsubtypes, or can be used as a tool to identify potential therapeuticagents for the treatment of diseases or conditions associated withabnormal activation of metabotropic glutamate receptors, by contactingsaid agents with said ligand-receptor complexes, and measuring theextent of displacement of the ligand and/or binding of the agent.

[0024] The invention also provides compounds of formula I comprising alabel (e.g a detectable radionuclide such as ³H, ¹¹C, ₁₄C, or ¹³N, or adetectable nonradioactive nuclide such as ²H, ¹³C, ¹⁵N, or ¹⁸O), andtheir use e.g. in stuties of receptor function or in the elucidation ofthe structure, function or mechanism of competitive ligand interaction.Techniques and radionuclides suitable for labeling compounds for in vivoor in vitro detection are well known to the art.

BRIEF DESCRIPTION OF THE FIGURES

[0025]FIG. 1 Illustrates the synthesis of compounds of the invention.

[0026]FIG. 2 Illustrates the synthesis of an intermediate of formula 11.

[0027]FIG. 3 Illustrates the synthesis of an intermediate of formula 15.

[0028]FIG. 4 Illustrates the synthesis of an intermediate of formula 17.

[0029]FIG. 5 Shows biological data for compounds of the invention.

[0030]FIG. 6 Shows biological data for compounds of the invention.

[0031]FIG. 7 Shows biological data for compounds of the invention.

[0032]FIG. 8 Shows biological data for compounds of the invention.

[0033]FIG. 9 Illustrates the synthesis of compounds of the invention.

[0034]FIG. 10 Illustrates the synthesis of compounds of the invention.

[0035]FIG. 11 Shows ¹H-NMR data for compounds of the invention.

[0036]FIG. 12 Illustrates the synthesis of compounds of the invention.

[0037]FIG. 13 Illustrates the synthesis of compounds of the invention.

[0038]FIG. 14 Illustrates the synthesis of compounds of the invention.

[0039]FIG. 15 Illustrates the synthesis of compounds of the invention.

[0040]FIG. 16 Illustrates the synthesis of compounds of the invention.

DETAILED DESCRIPTION

[0041] The following definitions are used, unless otherwise described:halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, alkenyl, alkynyl,etc. denote both straight and branched groups; but reference to anindividual radical such as “propyl” embraces only the straight chainradical, a branched chain isomer such as “isopropyl” being specificallyreferred to. Aryl denotes a phenyl radical or an ortho-fused bicycliccarbocyclic radical having about nine to ten ring atoms in which atleast one ring is aromatic. Heteroaryl encompasses a radical attachedvia a ring carbon of a monocyclic aromatic ring containing five or sixring atoms consisting of carbon and one to four heteroatoms eachselected from the group consisting of non-peroxide oxygen, sulfur, andN(X) wherein X is absent or is H, OH, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,phenyl or benzyl, as well as a radical of an ortho-fused bicyclicheterocycle of about eight to ten ring atoms derived therefrom,particularly a benz-derivative or one derived by fusing a propylene,trimethylene, or tetrarethylene diradical thereto.

[0042] It will be appreciated by those skilled in the art that compoundsof the invention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase) and how to determine metabotropic glutamate receptoragonist activity using the standard tests described herein, or usingother similar tests which are well known in the art.

[0043] Specific and preferred values listed below for radicals,substituents, and ranges, are for illustration only; they do not excludeother defined values or other values within defined ranges for theradicals and substituents

[0044] Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl,isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;(C₃-C₆)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl; (C₃-C₆)cycloalkyl(C₁-C₆)alkyl can be cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or2-cyclohexylethyl; (C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, orhexyloxy; (C₂-C₆)alkenyl can be vinyl, allyl, 1-propenyl, isopropenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl;(C₂-C₆)alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-hexynyl, 2-hexynyl 3-hexynyl, 4-hexynyl, or 5-hexynyl; (C₁-C₆)alkanoylcan be acetyl, propanoyl or butanoyl; halo(C₁-C₆)alkyl can beiodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl,2-chloroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, or pentafluoroethyl;hydroxy(C₁-C₆)alkyl can be hydroxymethyl, 1-hydroxyethyl,2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl,1-hydroxybutyl, 4-hydroxybutyl, 1-hydroxypentyl, 5-hydroxypentyl,1-hydroxyhexyl, or 6-hydroxhexyl; (C₁-C₆)alkoxycarbonyl can bemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl; (C₁-C₆)alkylthiocan be methylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, pentylthio, or hexylthio; (C₁-C₆)alkanoyloxy can beformyloxy, acetoxy, propanoyloxy, butanoyloxy, isobutanoyloxy,pentanoyloxy, or hexanoyloxy; aryl can be phenyl, indenyl, or naphthyl;and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, pyrazinyl,tetrazolyl, pyridyl (or its N-oxide), thienyl, pyrimidinyl (or itsN-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or itsN-oxide).

[0045] A specific value for R¹ is hydrogen.

[0046] A specific value for R² is carboxy.

[0047] A specific value for R³ is hydrogen.

[0048] A specific value for R⁴ is carboxy or hydroxymethyl.

[0049] A specific value for R⁵ is carboxy.

[0050] A specific value for R⁶ is hydrogen

[0051] Specifically, R⁷, and R₈ are each hydrogen.

[0052] Specifically, R⁹, and R¹⁰ are each hydrogen.

[0053] Specifically, X can be absent. Another specific value for X isoxy, thio, sulfinyl, sulfonyl, or —N(R_(x))—, wherein R_(x) is hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, phenyl, benzyl, or benzyloxycarbonyl. Yetanother specific value for X is methylene (—CH₂—).

[0054] A specific value for each of R_(f) and R_(g) is hydrogen.

[0055] A specific compound is a compound of formula II:

[0056] wherein

[0057] R¹, R², R³, and R⁴, are each independently hydrogen, carboxy,tetrazolyl, —SO₂OH, —PO(OH)₂, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, (C₂-C6)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₂-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, cyano, halo, —CONR_(a)R_(b),—NR_(c)R_(d), —SR_(e), aryl, heteroaryl, aryl(C₁-C₆)alkyl, orheteroaryl(C₁-C₆)alkyl, wherein any aryl or heteroaryl may optionally besubstituted with 1, 2 or 3 substituents selected from the groupconsisting of halo, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, and carboxy;

[0058] R⁵ is carboxy, tetrazolyl, (C₁-C₆)alkoxycarbonyl, —SO₂OH or—PO(OH)₂;

[0059] R⁶ is hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, phenyl, benzyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkanoyl, or phenethyl;

[0060] X is absent, oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl(—SO₂—), —C(R_(f))(R_(g))—, or —N(R_(x))—, wherein R_(x) is hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, phenyl, benzyl, or benzyloxycarbonyl;

[0061] each R_(a) R_(b) and R_(e) is independently hydrogen,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl,heteroaryl, benzyl, or phenethyl;

[0062] each R_(c) or R_(d) is independently hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkanoyl,aryl, heteroaryl, benzyl, or phenethyl; or R_(c) and R_(d) together withthe nitrogen to which they are attached are triazolyl, imidazolyl,oxazolidinyl, isoxazolidinyl, pyrrolyl, morpholino, piperidino,pyrrolidino, pyrazolyl, indolyl, or tetrazolyl;

[0063] R_(f) and R_(g) are each independently hydrogen, carboxy,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₂-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, cyano, halo, —CONR_(h)R_(i), —NR_(j)R_(k), or—SR_(m), aryl, heteroaryl, aryl(C₁-C₆)alkyl, or heteroaryl(C₁-C₆)alkyl,wherein any aryl or heteroaryl may optionally be substituted with 1, 2or 3 substituents selected from the group consisting of halo, hydroxy,(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, cyano, nitro, trifluoromethyl, trifluoromethoxy,and carboxy; or R_(f) and R_(g) together are oxo (═O) or thioxo (═S);

[0064] each R_(h), R_(i), and R_(m) is independently hydrogen,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl,heteroaryl, benzyl, or phenethyl; and

[0065] each R_(j) or R_(k) is independently hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkanoyl,aryl, heteroaryl, benzyl, or phenethyl; or R_(j) and R_(k) together withthe nitrogen to which they are attached are triazolyl, imidazolyl,oxazolidinyl, isoxazolidinyl, pyrrolyl, morpholino, piperidino,pyrrolidino, pyrazolyl, indolyl, or tetrazolyl;

[0066] or a pharmaceutically acceptable salt thereof.

[0067] A specific group of compounds are compounds of formula I or IIwherein at least one of R¹, R², R³, and R⁴ is carboxy, tetrazolyl, or—SO₂OH.

[0068] A specific group of compounds are compounds of formula I or IIwherein R² and R⁵ are carboxy, and R¹ is hydrogen.

[0069] A specific group of compounds are compounds of formula I or IIwherein R² is carboxy and R¹, R³, and R⁴ are hydrogen.

[0070] A specific group of compounds are compounds of formula I or IIwherein R⁷ or R⁸ is hydrogen, and the other of R⁷ and R⁸ is other thanhydrogen.

[0071] A preferred compound is a compound of formula (I) wherein R¹, R²,R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are each independently hydrogen, carboxy,tetrazolyl, —SO₂OH, —PO(OH)₂, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy(C₁C₆)alkyl, (C₁-C₆)alkanoyl,(C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, cyano, halo, —CONR_(a)R_(b),—NR_(c)R_(d), —SR_(e), aryl, heteroaryl, aryl(C₁-C₆)alkyl,diaryl(C₁-C₆)alkyl, or heteroaryl(C₁-C₆)alkyl, wherein any aryl orheteroaryl may optionally be substituted with 1, 2 or 3 substituentsselected from the group consisting of halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, cyano,nitro, trifluoromethyl, trifluoromethoxy, and carboxy; R⁵ is carboxy,tetrazolyl, (C₁-C₆)alkoxycarbonyl, —SO₂OH, or —PO(OH)₂; R⁶ is hydrogen,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, phenyl,benzyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyl, or phenethyl; and X isabsent (a direct or single bond connects C₃ and C₄), oxy (—O—), thio(—S—), sulfinyl (—SO—), sulfonyl (—SO₂—), —C(R_(f))(R_(g))—, or—N(R_(x))—, wherein R_(x) is hydrogen, (C₁-C₆)alkyl,(C₁-C₆)alkanoyl,phenyl, benzyl, or benzyloxycarbonyl; or a pharmaceutically acceptablesalt thereof; wherein at least one of R¹, R², R³, R⁴, R⁹, and R¹⁰ iscarboxy, tetrazolyl, —SO₂OH, or —PO(OH)₂.

[0072] A preferred compound is a compound of formula I wherein R⁷ and R⁸are each hydrogen.

[0073] A preferred compound is a compound of formula II wherein R¹, R²,R³, and R⁴, are each independently hydrogen, carboxy, tetrazolyl,—SO₂OH, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₁-C₆)alkoxycarbonyl, phenyl, benzyl, benzyloxy, phenethyl, cyano,mercapto, (C₁-C₆)aklylthio, or halo; R⁵ is carboxy, tetrazolyl,(C₁-C₆)alkoxycarbonyl, or —SO₂OH; and R⁶ is hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, phenyl, benzyl,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyl, or phenethyl; and X is absent;or a pharmaceutically acceptable salt thereof.

[0074] A preferred compound is a compound of formula I or II wherein R²and R⁵ are carboxy and X is absent.

[0075] A preferred compound of the invention is a compound of formulaIII:

[0076] or a pharmaceutically acceptable salt or prodrug thereof.

[0077] Processes for preparing compounds of formula I are provided asfurther embodiments of the invention and are illustrated by thefollowing procedures in which the meanings of the generic radicals areas given above unless otherwise qualified. A compound of formula Icomprising one or more carboxy groups may be prepared from acorresponding compound comprising one or more (C₁-C₆)alkoxycarbonylgroups, by hydrolysis. Conditions suitable for ester hydrolysis are wellknown to the art. For example, the hydrolysis may conveniently becarried out under conditions similar to those described in Example 1.

[0078] Compounds of formula I may also be prepared using the syntheticmethods described in Example 1 hereinbelow, or using the methods ormodifications of the methods outlined in Schemes 1 and 2 and in FIGS. 1,2, 3, 4, 9, 10, and 12-16. The starting materials employed in thesynthetic methods described herein are commercially available or arereported in the scientific literature.

[0079] Compounds of formula I, where X is oxy, thio, or —N(R_(x))—, canbe prepared using the synthetic methods illustrated in FIG. 1.Esterification of the carboxyl group of an intermediate of formula 11(X═O), 15 (X═NCbz), or 17 (X═S), followed by replacement of the hydroxylgroup adjacent to X with a phenylseleno group under acidic conditionsyields a compound of formula 18. Oxidation of selenide to selenoxideresults in spontaneous elimination (M. Kassou et al., Tetrahedron Lett.,35, 5513 (1994) to yield an allylic alcohol 19, which can be subjectedto an amide acetal Claisen rearrangement, to give an amide 20. Aftersaponification of the methyl esters, bromolactonization (I. Shibata etal., J. Org. Chem., 55, 2487 (1990), followed by tin hydridedehalogenation gives β-lactone 22. Closure of the cyclobutane ring usingthe β-lactone as the alkylating agent is achieved by treatment with astrong base, e.g., LDA, to produce a mixture of stereoisomers 23 and 24which can be separated. Amide hydrolysis followed by hydrogenolyticremoval of the N-benzyl and N-Cbz groups, gives compounds of theinvention 25 and 26.

[0080] Compounds of formula I wherein X is sulfinyl or sulfonyl can beprepared from corresponding compounds of formula I wherein X is thio, byoxidation, using reagents and techniques which are well known in theart.

[0081] An intermediate useful for preparing a compound of formula I,wherein X is oxy, is the hemiacetal 11. Hemiacetal 11 can be preparedfrom the oxazolidine 8 (prepared from D-serine in the same way as itsenantiomer is prepared from L-serine: E. J. Corey et al., J. Am. Chem.Soc., 114, 10677 (1992) as shown in FIG. 2. Hydroxyalkylation with themonoethylene acetal of malondialdehyde gives an alcohol of formula 9 asthe predominant stereoisomer. Acidic removal of the neopentylidenegroup, followed by protection of the amine as the Cbz derivative gives adiol of formula 10, which can be hydrolyzed with aqueous acid to givehemiacetal 11.

[0082] An intermediate useful for preparing a compound of formula I,wherein X is —N(R_(x))— is the hemiaminal 15, which can be prepared asshown in FIG. 3. Formation of the cyclic sulfate 12 from diol 10followed by nucleophilic displacement with sodium azide, and reductionof the azide to the primary amine gives the acetal 14, which can byhydrolyzed to give hemiaminal 15.

[0083] An intermediate useful for preparing a compound of formula I,wherein X is thio is the hemithioacetal 17, which can be prepared asshown in FIG. 4. Formation of the cyclic sulfate 12 from the diol 10,followed by nucleophilic displacement with potassium thioacetate, anddeacetylation with methoxide gives the acetal 16, which can behydrolyzed to give the hemithioacetal 17.

[0084] Procedures and intermediates useful for preparing compounds ofthe invention are also illustrated in FIGS. 12-16. Compound of formula34, 39, or 41 can be prepared from an aldehyde of formula 27 asillustrated in FIGS. 12 and 13. Alkylation of 27 with methallyl bromidefurnishes compound 28, and the second bridgehead methyl group isintroduced by Grignard reaction of the aldehyde derived by oxidation ofintermediate 29. To achieve dialkylation in position 3, for compounds 39and 41, α-alkylation of 27 with a tertiary allylic group reacting at itsmore highly substituted terminus is required. Although such atransformation may be difficult to achieve directly, it can be achievedusing an indirect sequence consisting of transesterification usingtitanium tetraisopropoxide to give compound 35 and Claisen rearrangementto give compound 36. The introduction of substituents in position 6 isachieved by ozonolytic cleavage of the double bond in intermediate 37,followed by Wittig reaction. The compounds 34, 39, and 41, can then beprepared using a sequence analogous to that depicted in Scheme 1.

[0085] A Compound of formula 54 or 67 can be prepared as illustrated inFIGS. 14 and 15. As photolysis of 1,6-heptadienes leads verypredominantly to parallel rather than crossed cycloadditionregiochemistry (i.e., formation of bicyclo[3.2.0]heptanes), the targetshave to be accessed instead through ring enlargement of appropriatelyfunctionalized bicyclo[2.1.1]hexane precursors. The use of a carbonylgroup in position 2 permits 1) the convenient assembly of the photolysissubstrates (compounds 43, 56); 2) the execution of a ring enlargementsequence (45 to 48, and 57 to 61) based upon enol silyl ether formation,cyclopropanation, and oxidative cleavage of the resultingsilyloxycyclopropane; 3) introduction of an alkyl group into the futureposition 4 via enolate alkylation (44 to 45); and 4) establishment ofthe amino acid functionality through a Bucherer-Bergs reaction (49 to51/52, and 62 to 64/65). The remote carboxyl group in both of thesesequences is preferentially introduced in masked form as phenyl, sincethe starting material cinnamaldehyde is much more accessible than estersof fumaraldehydic acid or maleinaldehydic acid, but those latter twotypes of compounds can also be used. Phenyl has to be oxidativelydegraded to carboxyl, which purpose can be achieved using Sharpless'system consisting of a catalytic amount of a ruthenium compound andsodium metaperiodate as stoichiometric oxidant. In the last step, thehydantoin is hydrolytically cleaved to reveal the free amino acid.Separations of stereoisomers are necessary at various stages because ofstereochemical ambiguity both at the carboxyl-bearing carbons as well asat monoalkylated methylene groups. Additionally, the compounds of FIGS.14 and 15 are obtained in racemic form and may be separated into theirenantiomers through techniques, such as HPLC on chiral columns or theformation of diastereomeric derivatives, which can be separatedchromatographically or by fractional crystallization and from which thedesired amino acids can be recovered hydrolytically. These separationtechniques are well known in the art.

[0086] The preparation of tetrazole 72 and phosphonic acid analogue 75are illustrated in FIG. 16. The general approach is the same as inScheme 1, but the second methoxycarbonyl group entering the moleculethrough a Wittig reaction is replaced by cyano (compound 68) ordiethoxyphosphoryl (compound 73); in the latter case, the syntheticprotocol used is a Wadsworth-Emmons rather than a Wittig reaction. Afterthe photochemical step, the tetrazole is elaborated from the cyano groupby reaction with trimethylsilyl azide and trimethylaluminum.

[0087] The modifications to the compounds shown in FIGS. 12 through 16can be implemented singly or in combination with each other; e.g.,alkylation in more than one position can be achieved by adjustment ofthe building blocks used, or the tetrazole analogue of compound 54 canbe prepared by transforming the free carboxyl group through routinemethods into cyano and applying the procedure of the foregoing paragraphto this intermediate. Furthermore, alkylation is not restricted tomethylation but may in an entirely analogous fashion be performed usinglarger alkyl groups or even functionalized alkyl groups, in which casestandard protecting groups are used to temporarily block reactivefunctionality.

[0088] In cases where compounds are sufficiently basic or acidic to formstable nontoxic acid or base salts, administration of the compounds assalts may be appropriate. Examples of pharmaceutically acceptable saltsare organic acid addition salts formed with acids which form aphysiological acceptable anion, for example, tosylate, methanesulfonate,acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including hydrochloride, sulfate, nitrate, bicarbonate,and carbonate salts.

[0089] Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

[0090] The term “prodrug” is well known in the pharmaceutical arts. Asused herein, the term includes compounds that are converted in vivo to acompound of formula I or II, or a salt thereof. The prodrugs of theinvention include derivatives that are known in the art to function asprodrugs, e.g., esters of an acid of formula I or II.

[0091] The compounds of formula I can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, i.e., orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes.

[0092] Thus, the present compounds may be systemically administered,e.g., orally, in combination with a pharmaceutically acceptable vehiclesuch as an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

[0093] The tablets, troches, pills, capsules, and the like may alsocontain the following: binders such as gum tragacanth, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; and a sweeteningagent such as sucrose, fructose, lactose or aspartame or a flavoringagent such as peppermint, oil of wintergreen, or cherry flavoring may beadded. When the unit dosage form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier, such as avegetable oil or a polyethylene glycol. Various other materials may bepresent as coatings or to otherwise modify the physical form of thesolid unit dosage form. For instance, tablets, pills, or capsules may becoated with gelatin, wax, shellac or sugar and the like. A syrup orelixir may contain the active compound, sucrose or fructose as asweetening agent, methyl and propylparabens as preservatives, a dye andflavoring such as cherry or orange flavor. Of course, any material usedin preparing any unit dosage form should be pharmaceutically acceptableand substantially non-toxic in the amounts employed. In addition, theactive compound may be incorporated into sustained-release preparationsand devices.

[0094] The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

[0095] The pharmaceutical dosage forms suitable for injection orinfusion can include sterile aqueous solutions or dispersions or sterilepowders comprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form must be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

[0096] Sterile injectable solutions are prepared by incorporating theactive compound in the required amount in the appropriate solvent withvarious of the other ingredients enumerated above, as required, followedby filter sterilization. In the case of sterile powders for thepreparation of sterile injectable solutions, the preferred methods ofpreparation are vacuum drying and the freeze drying techniques, whichyield a powder of the active ingredient plus any additional desiredingredient present in the previously sterile-filtered solutions.

[0097] For topical administration, the present compounds may be appliedin pure form, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

[0098] Useful solid carriers include finely divided solids such as talc,clay, microcrystalline cellulose, silica, alumina and the like. Usefulliquid carriers include water, alcohols or glycols orwater-alcohol/glycol blends, in which the present compounds can bedissolved or dispersed at effective levels, optionally with the aid ofnon-toxic surfactants. Adjuvants such as fragrances and additionalantimicrobial agents can be added to optimize the properties for a givenuse. The resultant liquid compositions can be applied from absorbentpads, used to impregnate bandages and other dressings, or sprayed ontothe affected area using pump-type or aerosol sprayers.

[0099] Thickeners such as synthetic polymers, fatty acids, fatty acidsalts and esters, fatty alcohols, modified celluloses or modifiedmineral materials can also be employed with liquid carriers to formspreadable pastes, gels, ointments, soaps, and the like, for applicationdirectly to the skin of the user.

[0100] Examples of useful dermatological compositions which can be usedto deliver the compounds of formula I to the skin are known to the art;for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S.Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman(U.S. Pat. No. 4,820,508).

[0101] Useful dosages of the compounds of formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

[0102] Generally, the concentration of the compound(s) of formula I in aliquid composition, such as a lotion, will be from about 0.1-25 wt-%,preferably from about 0.5-10 wt-%. The concentration in a semi-solid orsolid composition such as a gel or a powder will be about 0.1-5 wt-%,preferably about 0.5-2.5 wt-%. Single dosages for injection, infusion oringestion will generally vary between 50-1500 mg, and may beadministered, i.e., 1-3 times daily, to yield levels of about 0.5-50mg/kg, for adults.

[0103] The ability of a compound of the invention to act a modulator(i.e. an agonist, antagonist or partial agonist) of metabotropicglutamate receptors may be determined using pharmacological models whichare well known to the art, or using Test A described below.Additionally, the selectivity of a compound of the invention for aspecific metabotropic glutamate receptor Group or subtype may also bedetermined using Test A.

[0104] Test A.

[0105] Chinese hamster ovary (CHO) cells were used to produce cell linesexpressing mGluR1a and mGluR5a (Group 1), mGluR2 (Group II), mGluR6(Group III) receptors, as well as the chimeric receptor mGluR3/1a whichcombines the pharmacological properties of mGluR3 (Group II) with theactivation of phospholipase C The mGluR4 receptor (Group III) wasexpressed in baby hamster kidney (BHK) cells.

[0106] The activity of new compounds at phospholipase Coupled receptors(mGluR1a, mGluR5a, and mGluR3/1a) was determined by measurement of theirability to increase the hydrolysis of membrane phosphoinositides. CHOcells expressing mGluR1, mGluR5 or mGluR3/1a cultured in 96-well plateswere incubated overnight in glutamine-free culture medium supplementedwith 0.75 μCi myo-[³H]inositol to label the cell membranephosphoinositides. Before the experiments cells were washed 2 times with0.5 mL of Locke's solution (156 mM NaCl, 5.6 mM KCl, 3.6 mM NaHCO₃, 1 mMMgCl₂, 1.3 mM CaCl₂, 5.6 mM glucose and 20 mM Hepes, pH 7.4) followed byaddition of the same solution with 20 mM LiCl to block the degradationof inositol phosphates. Then receptor ligands were added, and the cellswere incubated for 40 minutes at 37° C. The reaction was terminated byaspiration of the medium, and inositol phosphates were extracted for 10minutes with 0.5 mL of 0.1 M HCl. The separation of [³H]inositolphosphates was performed by anion exchange chromatography. To thecollected fractions was added 10 mL of scintillation fluid, and theradioactivity was measured. In each experiment the stimulations inducedby the various compounds were normalized to the maximal response inducedby 1 mM glutamate and are expressed as per cent of maximal response.

[0107] The activity of a compound of the invention at receptors couplednegatively to adenylyl cyclase (mGluR2, mGluR4, mGluR6) was determinedby measurements of its ability to decrease the forskolin-inducedelevation of cyclic AMP formation. Cells expressing these receptors werecultured on 96-well culture plates. Before experiments, cells werewashed three times and preincubated 10 minutes at 37° C. in Locke'smedium containing 300 μM isobutylmethylxanthine to inhibit the activityof phosphodiesterases which degrade cAMP. Then 5 or 10 μM forskolin wasadded without or with mGluR agonists, and the incubation was continuedfor 10 minutes. After the incubation, the medium was rapidly aspiratedand cAMP was extracted for 10 minutes with 0.1 M HCl and measured byradioimmunoassay using a magnetic Amerlex RIA kit. Within eachexperiment the results were normalized to the maximal response inducedby 1 mM glutamate for mGluR2 and mGluR4, and by 1 mM4-aminophosphonobutyrate for mGluR6, and are expressed as per cent ofmaximal response.

[0108] The evaluation of the relative potencies of the tested compoundsand the determination of their EC₅₀ values was performed by fitting thenormalized data to the logistic equation by non-linear regression.

[0109] Experimental results from Test A for representative compounds ofthe invention (prepared as described in Example 1) are shown in FIG. 5.These results demonstrate that compounds of the invention are agonistsof metabotropic glutamate receptors. In particular, the representativecompounds tested showed selectivity for the Group II receptor mGluR2.

[0110] Based on the specific binding of the compounds of the inventionto glutamate receptors and their agonist, partial agonist or antagonistactivity, the compounds of the invention should have a number oftherapeutic uses. For example, an appropriate amount of a compound offormula I can be administered to a subject to prevent or treat (e.g.,alleviate the symptoms or slow the progression of) a condition ordisorder that is linked (e.g., involves signaling) from metabotropicglutamate receptors, including neurological, neurodegenerative,psychiatric and psychological disorders. Examples of these conditions ordiseases include: epilepsy, cerebral deficits subsequent to cardiacbypass surgery and grafting, stroke, cerebral ischemia, pain, spinalcord injury, head trauma, perinatal hypoxia, cardiac arrest andhypoglycemic damage, anxiety and neurodegenerative diseases such as LouGehrig's disease (ALS), Huntington's Chorea, AIDS-induced dementia,ocular damage and retinopathy, cognitive disorders, Parkinson's Disease,and Multiple Sclerosis, as well as other conditions that result inprogressive loss of neuronal cells and/or cellular function.

[0111] The compounds of the invention can also be administered to asubject in order to treat or manage an addiction, e.g., to drugs,including narcotics, cocaine, alcohol, benzodiazepine, nicotine), foodsor other substances.

[0112] Additionally, compounds of the invention may be useful aspharmacological tools for the further investigation of mGluR function.

[0113] For use in therapy or treatment, an effective amount of thecompound of formula I, a prodrug thereof, or a pharmaceuticalpreparation thereof (e.g., a formulation that facilitates passagethrough the blood brain barrier or that slows down in vivo metabolism)can be administered to a subject in accordance with any method thatallows the compound to be taken up by the appropriate organ and performits intended function. Preferred routes of administration include oral,intravenous and transdermal (e.g., via a patch) administration.

[0114] In addition to the above-described therapeutic uses, thecompounds of the invention may be labeled (e.g., radioactively using ³H,¹¹C, ¹⁴C or ¹³N, or non-radioactively using ²H, ¹³C, ¹⁵N or ¹⁸O) andused in research, for example, for studies on receptor function or toelucidate the structure, function or mechanisms of competitive ligandinteractions. In addition, labeled compounds can be useful fordetermining the selectivity, specificity, or potency of novel clinicalentities directed at the glutamate receptor. Further, the compounds canbe useful for testing competing compounds for the ability to interactwith a member of the glutamate receptor family (i.e., in a competitivebinding assay).

[0115] Generally, compounds of the invention are metabotropic glutamatereceptor ligands, i.e., are capable of binding to metabotropic glutamatereceptors. As a result, they may demonstrate agonist, antagonist, orpartial agonist activity at these receptors. The use of expressioncloning techniques has led to the identification of eight mGluRsubtypes, which have been placed into three major categories based ontheir molecular structure, signal transduction mechanisms, andpharmacological properties. Compounds demonstrating agonist, antagonist,or partial agonist activity at Group I, II, or III receptors are usefulas described herein, as pharmacological tools or as therapeutic agents.Compounds demonstrating selectivity for one or more receptor sub-typesare similarly useful. For therapeutic uses, compounds demonstratingantagonist activity at Group I receptors, or compounds demonstratingagonist or partial agonist activity at Group II or Group III receptorsmay be preferred.

[0116] The invention will now be illustrated by the followingnon-limiting Examples.

EXAMPLE 1.

[0117] As illustrated in Scheme 1, oxazolidine 1 was produced using aprocedure similar to that described in Helv. Chim. Acta. 1987, 70, 1194.Treatment of 1 with HCl in methanol afforded α-allylserine methyl esterwhich was protected with benzyl chloroformate to give compound 2. Thealcohol was oxidized under Swern conditions and the resulting aldehydetreated with methyl (triphenylphosphoranylidene)acetate to produce theα,β-unsaturated ester 3.

[0118] As illustrated in Scheme 2, diene 3 was irradiated in thepresence of acetophenone using either a quartz or Pyrex apparatus.Compounds 4 a-c were isolated as a chromatographically homogeneousmixture while 4d was isolated as a single compound (a-d indicates thecompound's relative polarity with a being the least polar). The mixtureof compounds (4 a-c) was deprotected with Pd/C under all atmosphere ofH₂ to afford compounds 5 a-c as three separable compounds. Compound 4dwas also deprotected using H2 and Pd/C. The diesters 5 a-d, which arealso compounds of the invention, were individually treated with 6N HClat reflux for 1 hour to afford the diacid compounds of the invention 6a-d.

[0119] (2S)-2-Allylserine Methyl Ester (2). Acetyl chloride (460 mL,6470 mmol) was added via addition funnel to methanol (1080 mL) at 0° C.A solution of 1 (18.3 g, 71.8 mmol) in methanol (10 mL) was added andthe reaction mixture refluxed for 3 hours. Evaporation of the volatilesin vacuo produced a white solid which was dissolved in dioxane (150 mL)and H₂O (50 mL). NaHCO₃ (12.1 g, 144 mmol) and benzyl chloroformate(20.5 mL, 144 mmol) were added, and the reaction mixture was stirredovernight. The reaction mixture was extracted with EtOAc (3x), and thecombined organic phases were washed with brine, dried over MgSO₄,filtered and concentrated. Column chromatography (SiO₂, EtOAc-hexanegradient elution) afforded 2 (12.25 g, 58%) as a colorless oil: [α]^(RT)_(D)-0.4° (c2.1, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ7.37-7.29 (m, 5H),5.79 (br s, 1H), 5.68-5.52 (m, 1H), 5.15-5.01 (m, 4H), 4.18-4.07 (m,1H), 3.88-3.76 (m, 1H), 3.75 (s, 3H), 3.51 (br s, 1H), 2.78 (dd, J=13.8,7.8 Hz, 1H), 2.52 (dd, J=14.1, 7.2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃)δ172.25, 155.24, 135.95, 131.02, 128.36, 128.04, 127.90, 119.91, 66.69,65.08, 64.93, 52.73, 36.73; IR (film) v_(max) 3407, 1724 cm⁻¹.

[0120] Compound 3. A solution of DMSO (0.57 mL, 7.8 mmol) in CH₂Cl₂ (8mL) was added at −78° C. to a solution of oxalyl chloride (0.51 mL, 5.9mmol) in CH₂Cl₂ (4 mL) over 15 minutes. Alcohol 2 (1.15 g, 3.95 mmol) inCH₂Cl₂ (20 mL) was added at −78° C. over 10 minutes. After stirring foran additional 10 minutes, Et₃N (2.73 mL, 19.6 mmol) in CH₂Cl₂ (15 mL)was added over 10 minutes and the temperature maintained between −60° C.and −70° C. for 30 minutes. The reaction mixture was quenched with asaturated solution of NH₄Cl and extracted with CH₂Cl₂ (5x). The combinedorganic fractions were dried over MgSO₄, filtered and concentrated. Theresidue was dissolved in CH₂Cl₂ (45 mL), methyl(triphenylphosphoranylidene)acetate (1.97 g, 5.88 mmol) was added, andthe mixture was stirred at RT for 4 h. The reaction mixture was thenpoured into H₂O and extracted with CH₂Cl₂ (5x) The combined organicfractions were dried over MgSO₄, filtered and concentrated. Purificationof the residue by column chromatography (SiO₂, 33% EtOAc-hexane)afforded compound 3 (1.36 g, quant.) as a colorless oil: [α]^(RT)_(D)-2.2° (c 1.6, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ7.41-7.27 (m, 5H),7.16 (d, J=15.9 Hz, 1H), 5.98 (d, J=15.9 Hz, 1H), 5.73 (br s, 1H),5.65-5.50 (m, 1H), 5.20-5.00 (m, 4H), 3.78 (s, 3H), 3.74 (s, 3H), 2.89(dd, J=13.2, 6.6 Hz, 1H), 2.67 (dd, J=13.5, 7.5 Hz, 1H); ¹³C NMR (75MHz, CDCl₃) δ170.80, 166.18, 154.21, 145.33, 136.02, 130.43, 128.47,128.18, 128.10, 121.47, 120.86, 66.91, 63.20, 53.26, 51.71, 40.26; IR(film) v_(max) 3352, 1724 cm⁻¹.

[0121] Compounds 4 a-d. Diene 3 (3.84 g, 11.52 mmol) and acetophenone(0.40 mL) in benzene (400 mL) were first purged with argon and thenirradiated with a Hanovia 450 W medium pressure mercury lamp through aPyrex filter. After 4.5 days, the reaction mixture was evaporated andthe residue purified by column chromatography (SiO₂, 33% EtOAc-hexanes)to afford a mixture of cis- and trans-3 (R_(f)0.8, 50% EtOAc-hexanes,1.16 g, 30%), 4 a-c (R_(f)0.65, 50% EtOAc-hexanes, 1.22 g, 32%) and 4d.

[0122] colorless oil; yield 197 mg (5%); R_(f)0.53 (EtOAc/hexanes 1/1);¹H NMR (CDCl₃) δ7.33-7.27 (m, 5H), 5.63 (br s, 1H), 5.06 (br s, 2H),3,59 (br, s 6H), 3.18 (br s, 1H), 3.04 (d, J=12.3 Hz, 1H), 2.72-2.69 (m,1H), 1.77 (d, J=12.3 Hz, 1H), 1.53-1.50 (m, 1H), 1.41 (d, J=7.2 Hz, 1H);¹³C NMR (75 MHz, CDCl₃) δ172.36 (C), 170.51 (C), 155.22 (C), 136.06 (C),128.36 (CH), 128.03 (CH), 66.75 (CH₂), 63.34 (C), 52.17 (CH₃), 51.32(CH), 51.17 (CH₃), 49.61 (CH), 39.81 (CH), 37.08 (CH₂), 36.11 (CH₂).

[0123] Compounds 5 a-c. Compounds 4 a-c (520 mg, 1.50 mmol) and 10% Pd/C(80 mg) were stirred in MeOH (25 mL) under an atmosphere of H₂. After 3hours, the reaction mixture was filtered and concentrated. Silica gelcolumn chromatography (11% MeOH-EtOAc) of the crude mixture gave thecompounds 5 a-c.

[0124] yield 64 mg (20%); R_(f)0.80; ¹H NMR (CDCl₃) δ1.07 (d, J=7.5 Hz,1H), 1.46-1.56 (m, 1H), 1.67 (br s, 2H), 1.97 (dd, J=2.1 and 11.4 Hz,1H), 2.35 (d, J=11.4 Hz, 1H), 2.61 (s, 1H), 2.64-2.74 (m, 1H), 2.9-3.0(m, 1H), 3.60 (s, 3H), 3.71 (s, 3H); ¹³C NMR (CDCl₃) δ36.4, 36.6, 39.7,49.4, 50.9, 52.0, 52.6, 63.3, 172.4, 176.4.

[0125] yield 65 mg (20%); R_(f)0.6; ¹H NMR (CDCl₃) δ1.29 (t, J=8.1 Hz,H₆), 1.54 (dd, J=2.4 and 11.7 Hz, H₃), 1.77 (bs, NH₂), 2.2-2.3 (m, H₆),2.47 (d, J=11.7 Hz, H₃, 2.64-2.74 (m, H₄), 2.77 (dd, J=2.7 and 6.9 Hz,H₁), 3.01 (d, J=7.8 Hz, H₅), 3.73 (s, 3H), 3.74 (s, 3H); ¹³C NMR (CDCl₃)δ37.6 (C₆), 39.9 (C₃), 41.6 (C₄), 51.6 (Me), 51.7 (Me), 52.1 (C₁), 52.8(C₅), 63.3 (C₂), 173.7 (CO), 176.1 (CO).

[0126] yield 156 mg (49%); R_(f)0.49; ¹H NMR (CD₃OD) δ1.54 (dd, J=0.9and 12.0 Hz, H₃), 1.72 (t, J=8.1 Hz, H₆), 2.26 (ddd, J=2.7, 5.4 and 8.1Hz, H₆), 2.51 (d, J=8.1 Hz, H₅), 2.28-2.38 (m, 1H), 2.5-2.57 (m, H₄),2.72 (dd, J=2.4 and 6.9 Hz, H₁), 3.68 (s, 3H), 3.74 (s, 3H), 4.82 (br s,NH₂); ¹³C NMR (CD₃OD) δ36.9 (C₆), 41.3 (C₃), 42.9 (C₄), 52.4 (Me), 53.0(Me), 54.0 (C₁), 55.5 (C₅), 64.5 (C₂), 172.8 (CO), 175.9 (CO).

[0127] Compound 4d (95 mg, 0.27 mmol) and 10% Pd/C (15 mg) were stirredin MeOH (5 mL) under an atmosphere of H2. After 3 h, the reactionmixture was filtered and concentrated. Purification of the residue bycolumn chromatography (SiO₂, 11% MeOH-EtOAc) afforded compound 5d (58mg, 100%) as a colorless oil. ¹H NMR (CDCl₃) δ1.46 (d, J=11.7 Hz, 1H),1.5-1.6 (m, 1H), 1.62 (d, J=7.2 Hz, 1H), 1.85 (br s, 2H), 2.63-2.70 (m,2H), 2.82 (dd, J=1.8 and 11.7 Hz, 1H), 2.87-2.94 (m, 1H), 3.56 (s, 3H),3.69 (s, 3H).

[0128] Compounds 6 a-d. Compound 5 a-d were treated with 6N HCl andstirred at reflux for 1 hour. Evaporation afforded compounds 6 a-d.

[0129]¹H NMR (D₂O) δ1.50 (d, J=8.1 Hz, 1H), 1.65-1.75 (m, 1H), 2.02 (dd,J=2.7 and 13.2 Hz, 1H), 2.70 (d, J=13.2 Hz, 1H), 2.9-3.0 (m, 1H), 3.06(bs, 1H), 3.1-3.2 (m, 1H).

[0130]¹H NMR (D₂O) δ1.86 (t, J=8.7 Hz, 1H), 2.03 (d, J=12.6 Hz, 1H),2.3-2.4 (m, 1H), 2.63 (d, J=12.6 Hz, 1H), 2.8-3.0 (m, 2H), 3.05-3.02 (m,1H).

[0131]¹H NMR (D₂O) δ1.65 (t, J=9.0 Hz, 1H), 2.01 (d, J=12.6 Hz, 1H),2.46 (dt, J=2.4 and 9.6 Hz, 1H), 2.63 (br, d J=12.9 Hz, 1H), 2.8-2.9 (m,1H), 3.08 (dd, J=2.4 and 6.9 Hz, 1H), 3.15 (d, J=8.7 Hz, 1H),

[0132]¹H NMR (D₂O) δ1.66 (t, J=9.3 Hz, 1H), 2.02 (d, J=12.6 Hz, 1H),2.4-2.5 (m, 1H), 2.65 (br d, J=12.9 Hz, 1H), 2.8-2.9 (m, 1H), 3.05-3.15(m, 1H), 3.18 (d, J=8.7 Hz, 1H).

EXAMPLE 2.

[0133] The following illustrate representative pharmaceutical dosageforms, containing a compound of formula I, for therapeutic orprophylactic use in humans. (i) Tablet 1 mg/tablet ‘Compound X’ 100.0 Lactose 77.5  Povidone 15.0  Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5  Magnesium stearate 3.0 300.0  (ii)Tablet 2 mg/tablet ‘Compound X’ 20.0  Microcrystalline cellulose 410.0 Starch 50.0  Sodium starch glycolate 15.0  Magnesium stearate 5.0 500.0 (iii.) Capsule mg/capsule ‘Compound X’ 10.0  Colloidal silicon dioxide1.5 Lactose 465.5  Pregelatinized starch 120.0  Magnesium stearate 3.0600.0  (iv) Injection 1 (1 mg/ml) mg/ml ‘Compound X’ (free acid form)1.0 Dibasic sodium phosphate 12.0  Monobasic sodium phosphate 0.7 Sodiumchloride 4.5 1.0 N Sodium hydroxide solution q.s. (pH adjustment to7.0-7.5) Water for injection q.s. ad 1 mL (v) Injection 2 (10 mg/ml)mg/ml ‘Compound X’ (free acid form) 10.0  Monobasic sodium phosphate 0.3Dibasic sodium phosphate 1.1 Polyethylene glycol 400 200.0  01 N Sodiumhydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injectionq.s. ad 1 mL (vi) Aerosol mg/can ‘Compound X’ 20.0  Oleic acid 10.0 Trichloromonofluoromethane 5,000.0    Dichlorodifluoromethane10,000.0    Dichlorotetrafluoroethane 5,000.0   

[0134] The above formulations may be obtained by conventional procedureswell known in the pharmaceutical art.

[0135] All publications, patents, and patent documents are incorporatedby reference herein, as though individually incorporated by reference.The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

What is claimed is:
 1. A compound of formula I:

wherein R¹, R², R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are each independentlyhydrogen, carboxy, tetrazolyl, —SO₂OH, —PO(OH)₂, —B(OH)₂, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, cyano, halo,—CONR_(a)R_(b), —NR_(c)R_(d), —SR_(e), aryl, heteroaryl,aryl(C₁-C₆)alkyl, diaryl(C₁-C₆)alkyl, or heteroaryl(C₁-C₆)alkyl, whereinany aryl or heteroaryl may optionally be substituted with 1, 2 or 3substituents selected from the group consisting of halo, hydroxy,(C₁-C₆)alkoxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, cyano, nitro, trifluoromethyl, trifluoromethoxy,and carboxy; R⁵ is carboxy, tetrazolyl, (C₁-C₆)alkoxycarbonyl, —SO₂OH,—B(OH)₂, or —PO(OH)₂; R⁶ is hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, heteroaryl,heteroaryl(C₁-C₆)alkyl, (C₁-C₆)alkoxycarbonyl, or (C₁-C₆)alkanoyl; X isabsent (a direct or single bond connects C₃ and C₄), oxy (—O—), thio(—S—), sulfinyl (—SO—), sulfonyl (—SO₂—), —C(R_(f))(R_(g))—, seleno(—Se—), —P(R_(x))—, or —N(R_(x))—, wherein R_(x) is hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, aryl, aryl(C₁-C₆)alkyl,(C₁-C₆)alkoxycarbonyl, or aryl(C₁-C₆)alkoxycarbonyl; each R_(a) R_(b)and R_(c) is independently hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heteroaryl, benzyl, or phenethyl;each R_(c) or R_(d) is independently hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkanoyl,aryl, heteroaryl, benzyl, or phenethyl; or R_(c) and R_(d) together withthe nitrogen to which they are attached are triazolyl, imidazolyl,oxazolidinyl, isoxazolidinyl, pyrrolyl, morpholino, piperidino,pyrrolidino, pyrazolyl, indolyl, or tetrazolyl; R_(f) and R_(g) are eachindependently hydrogen, carboxy, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, cyano, halo, —CONR_(h)R_(i),—NR_(j)R_(k), —SR_(m), aryl, heteroaryl, aryl(C₁-C₆)alkyl, orheteroaryl(C₁-C₆)alkyl, wherein any aryl or heteroaryl may optionally besubstituted with 1, 2 or 3 substituents selected from the groupconsisting of halo, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, and carboxy; or R_(f) and R_(g)together are oxo (═O) or thioxo (═S); each R_(h), R_(i), and R_(m) isindependently hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, aryl, heteroaryl, benzyl, or phenethyl; and each R_(j)or R_(k) is independently hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkanoyl, aryl, heteroaryl,benzyl, or phenethyl; or R_(j) and R_(k) together with the nitrogen towhich they are attached are triazolyl, imidazolyl, oxazolidinyl,isoxazolidinyl, pyrrolyl, morpholino, piperidino, pyrrolidino,pyrazolyl, indolyl, or tetrazolyl; or a pharmaceutically acceptable saltor prodrug thereof; wherein at least one of R¹, R², R³, R⁴, R⁹, and R₁₀is carboxy, tetrazolyl, —SO₂OH, —PO(OH)₂, or —B(OH)₂.
 2. The compound ofclaim 1 wherein R¹, R², R³, R⁴, R⁷, R⁸, R⁹ and R¹⁰ are eachindependently hydrogen, carboxy, tetrazolyl, —SO₂OH, —PO(OH)₂,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl,(C₁-C₆)alkanoyl, cyano, halo,—NR_(c)R_(d), aryl, heteroaryl, aryl(C₁-C₆)alkyl, diaryl(C₁-C₆)alkyl, orheteroaryl(C₁-C₆)alkyl, wherein any aryl or heteroaryl may optionally besubstituted with 1, 2 or 3 substituents selected from the groupconsisting of halo, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, and carboxy.
 3. The compound of claim1 wherein R¹, R², R³, R⁴, R⁷, R⁸, R⁹, and R¹⁰ are each independentlyhydrogen, carboxy, tetrazolyl, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkanoyl, cyano, halo, aryl, or heteroaryl, wherein any aryl orheteroaryl may optionally be substituted with 1, 2 or 3 substituentsselected from the group consisting of halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, cyano, nitro, trifluoromethyl, trifluoromethoxy,and carboxy.
 4. The compound of claim 1 wherein R⁵ is carboxy,tetrazolyl, (C₁-C₆)alkoxycarbonyl, —SO₂OH, or —PO(OH)₂.
 5. The compoundof claim 1 wherein R⁵ is carboxy.
 6. The compound of claim 1 wherein R⁶is hydrogen, (C₁-C₆)alkyl, aryl, aryl(C₁-C₆)alkyl, diaryl(C₁-C₆)alkyl,or (C₁-C₆)alkanoyl.
 7. The compound of claim 1 wherein X is absent. 8.The compound of claim 1 wherein X is oxy, thio, sulfinyl, sulfonyl or—N(R_(x))—.
 9. The compound of claim 1 wherein X is —C(R_(f))(R_(g))—.10. A compound of formula II:

wherein R¹, R², R³, and R⁴, are each independently hydrogen, carboxy,tetrazolyl, —SO₂OH, —PO(OH)₂, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₂-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, cyano, halo, —CONR_(a)R_(b),—NR_(c)R_(d), —SR_(c), aryl, heteroaryl, aryl(C₁-C₆)alkyl, orheteroaryl(C₁-C₆)alkyl, wherein any aryl or heteroaryl may optionally besubstituted with 1, 2 or 3 substituents selected from the groupconsisting of halo, hydroxy, (C₁-C₆)alkoxy, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, and carboxy; R⁵ is carboxy,tetrazolyl, (C₁-C₆)alkoxycarbonyl, —SO₂OH or —PO(OH)₂; R⁶ is hydrogen,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, phenyl,benzyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkanoyl, or phenethyl; X isabsent, oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—SO₂—),—C(R_(f))(R_(g))—, or —N(R_(x))—, wherein R_(x) is hydrogen,(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, phenyl, benzyl, or benzyloxycarbonyl;each R_(a) R_(b) and R_(c) is independently hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heteroaryl,benzyl, or phenethyl; each R_(c) or R_(d) is independently hydrogen,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)alkanoyl, aryl, heteroaryl, benzyl, or phenethyl; or R_(c) andR_(d) together with the nitrogen to which they are attached aretriazolyl, imidazolyl, oxazolidinyl, isoxazolidinyl, pyrrolyl,morpholino, piperidino, pyrrolidino, pyrazolyl, indolyl, or tetrazolyl;R_(f) and R_(g) are each independently hydrogen, carboxy, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl, (C₂-C₆)alkenyl,(C₂-C₆)alkynyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₂-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, cyano, halo,—CONR_(h)R_(i), —NR_(j)R_(k), or —SR_(m), aryl, heteroaryl,aryl(C₁-C₆)alkyl, or heteroaryl(C₁-C₆)alkyl, wherein any aryl orheteroaryl may optionally be substituted with 1, 2 or 3 substituentsselected from the group consisting of halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(C₁-C₆)alkyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, cyano,nitro, trifluoromethyl, trifluoromethoxy, and carboxy; or R_(f) andR_(g) together are oxo (═O) or thioxo (═S); each R_(h), R_(i), and R_(m)is independently hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, aryl, heteroaryl, benzyl, or phenethyl;and each R_(j) or R_(k) is independently hydrogen, (C₁-C₆)alkyl,(C₃-C₆)cycloalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)alkanoyl,aryl, heteroaryl, benzyl, or phenethyl; or R_(j) or R_(k) together withthe nitrogen to which they are attached are triazolyl, imidazolyl,oxazolidinyl, isoxazolidinyl, pyrrolyl, morpholino, piperidino,pyrrolidino, pyrazolyl, indolyl, or tetrazolyl; or a pharmaceuticallyacceptable salt thereof; wherein at least one of R¹, R², R³, and R⁴ iscarboxy, tetrazolyl, or —SO₂OH.
 11. The compound of claim 10 whereinwherein R¹, R², R³, and R⁴, are each independently hydrogen, carboxy,tetrazolyl, —SO₂OH, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, phenyl,benzyl, benzyloxy, phenethyl, cyano, mercapto, (C₁-C₆)alkylthio, orhalo; R⁵ is carboxy, tetrazolyl, (C₁-C₆)alkoxycarbonyl, or —SO₂OH; andR⁶ is hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl,(C₃-C₆)cycloalkyl(C₁-C₆)alkyl, phenyl, benzyl, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkanoyl, or phenethyl; and X is absent.
 12. The compound ofclaim 10 which is a compound of formula III:

or a pharmaceutically acceptable salt or prodrug thereof.
 13. Apharmaceutical composition comprising a compound of claim 1 incombination with a pharmaceutically acceptable carrier.
 14. Atherapeutic method for preventing or treating a pathological conditionor symptom in a mammal which is associated with abnormal activity of ametabotropic glutamate receptor, comprising administering to a mammal inneed of such therapy, an effective amount of a compound of claim
 1. 15.The method of claim 14 wherein the condition is, or the symptom isassociated with epilepsy, cerebral deficits subsequent to cardiac bypasssurgery and grafting, stroke, cerebral ischemia, pain, spinal cordinjury, head trauma, perinatal hypoxia, cardiac arrest and hypoglycemicdamage, anxiety, neurodegenerative diseases, Huntington's Chorea,AIDS-induced dementia, ocular damage, retinopathy, cognitive disorders,Parkinson's Disease, or Multiple Sclerosis.
 16. The method of claim 14wherein the condition results in progressive loss of neuronal cellsand/or cellular function.
 17. The method of claim 14 wherein thecondition is, or the symptom is associated with stroke.
 18. The methodof claim 14 wherein the condition is, or the symptom is associated withAlzheimer's disease.
 19. A therapeutic method to treat or manage anaddiction comprising administering an effective amount of a compound ofclaim 1 to a mammal in need of such therapy.
 20. The compound of claim 1comprising a detectable label.